Summary In contrast to other lung carcinomas, there has been no significant progress in the development of Small Cell Lung Cancer (SCLC) therapies since the introduction of chemotherapy in the 1970s. Although SCLC tumors exhibit a complex genome with a high mutation rate, genomic characterization of SCLC has not provided a clear pathway forward for the design of SCLC tailored therapy. Using an unbiased, high-throughput cellular screen of a diverse chemical library, we have identified that SCLC is highly sensitive to inhibitors of the general transcription apparatus. In particular, we observed that genetically engineered mouse (GEM) models of SCLC were highly sensitive to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7) that functions as a co-factor for RNA polymerase II (RNAPII). We identified a number of THZ1-sensitive transcripts: the focally amplified and/or transcriptionally amplified lineage-specific transcription factors (TFs) in SCLC cells. The TFs were associated with unusually large enhancer sequences - super-enhancers - that have been shown to be associated with key oncogenic factors cancer cells. Thus, we hypothesize that amplified and overexpressed lineage-specific transcription factors govern SCLC initiation and disease evolution, and downregulation of such factors could form the basis for SCLC targeted therapy. Based on a state-of-the art preclinical platform this proposal aims to explore the therapeutic potential of inhibitors that can modulate the general transcription apparatus and epigenetic state in SCLC. Further, we aim to investigate the malignant transcriptional circuits in SCLC biology to further guide drug discovery and therapeutic development for this malignant disease.